Metal-chelating agents have been used as contrast agents and have proven useful in magnetic resonance imaging ("MRI"), radionuclide imaging, ultrasound imaging and X-ray imaging. The overall effect of these contrast agents can be enhanced when the contrast agent is complexed with a metal ion, in particular a paramagnetic metal ion. However, the paramagnetic metal ions used are generally toxic and as a result only low dosages of the contrast agent containing paramagnetic metal ions can be administered. For example, gadolinium exhibits strong paramagnetic properties making it useful as the paramagnetic metal ion portion of the contrast agent complex. However, because any free gadolinium released from a contrast agent will accumulate in the bone marrow, liver and spleen, with resulting toxicity, gadolinium cannot be used to enhance a contrast agent unless it is complexed with a strong chelating agent.
Over the last several years, a number of contrast agents have been proposed for magnetic resonance imaging of the liver. These contrast agents include gadolinium-diethylene triamino pentaacetic acid ("Gd-DTPA") (Venetia et al., "Magnetic Resonance Imaging of the Liver", Top Magnetic Resonance Imaging 1990; 2:1-16); iron ethylene bis (2-hydroxy phenyl glycine) ("Fe-EHPG") (Shtern et al., "MR Imaging of Blood-borne Liver Metastasis in Mice: Contrast Enhancement With Fe-EHPG, Radiology 1991; 178:83-89), gadolinium-hepatic iminodiacetic acid ("Gd-HIDA") (Engelstad et al., "Hepatobiliary Magnetic Resonance Contrast Agents Assessed by Gadolinium-153 Scintigraphy", Invest Radiol. 1987; 22:232-238), gadolinium-benzyloxyproprionyl tetracetate ("Gd-BOPTA") (Pavone et al., "Comparison of Gd-BOPTA with Gd-DTPA in MR Imaging of Rat Liver", Radiology 1990; 176:61-64); and manganese-ethylene dipyridoxal diphosphate ("Mn-DPDP") (Elezondo et al., "Preclinical evaluation of Mn-DPDP: New paramagnetic hepatobiliary contrast agent for MR Imaging", Radiology 1991; 178:83-78).
The liver is known to contain more hepatocytes (78% by volume) than reticuleoendothelial cells (2% by volume) and therefore it is preferable to administer a contrast agent which will initially localize in hepatocytes and which will ultimately be quantitatively excreted in the bile with no resulting long term hepatic or total body retention.
Of the above-mentioned contrast agents, Gd-DTPA has been found not to be suitable for MRI of the liver because of its rapid clearance from the blood and subsequent prompt renal excretion. The other hepatocyte-localizing agents have been found to have low hepatic concentration. For example, the liver concentrates only 37% of the injected dose of Gd-BOPTA, while Mn-DPDP localizes only 47% in the liver. Additionally, up to 6% of manganese is retained in the body after 7 days (Saud et al., "Occlusive and reperfused myocardial infarcts: Differentiation with Mn-DPDP enhanced MR Imaging", Radiology 1989; 172:59-64) Moreover, the Gd-HIDA analysis described in the literature, the gadolinium has been found to be loosely bound to the iminodiacetic acid chelating agent. This minimizes the in vivo stability of the contrast agent during hepatocellular concentration, hepatobiliary excretion and its ultimate elimination from the body.
Nuclear imagers have known for many years that hepatic parenchymal uptake of Tc-99m labeled hepatobiliary agents (HIDA) is greater than that of hepatic metastases. One could reason that MRI of the liver with a new hepatobiliary agent, which has gadolinium substituted for technetium may improve tumor/parenchymal differentiation, given the superior spatial resolution of MRI. However, Gd-HIDA and derivatives thereof, have failed to enhance the image of the gall bladder and have only faintly enhanced images of the liver. Additionally, these compounds have proven unstable in vivo, resulting in the release of gadolinium which is retained in the liver, spleen and bone marrow at excessive and potentially toxic levels.
The present invention relates to a new group of compounds which can be used as metal chelating agents. These compounds when complexed with metal ions, especially paramagnetic metal ions, form new complexes with improved and unexpected stability making them useful as contrast agents in MRI and other types of diagnostic imaging.
An object of this invention is to provide new and improved compounds which can be used as metal chelating agents. A further object of this invention is to provide metal chelating agents which when complexed with metal ions, and in particular paramagnetic metal ions, form new complexes with improved stability. Another object of this invention is to provide metal chelating agents which can be used as an MRI contrast agent which can be administered in lower dosages. Additionally, a further object of this invention is to provide MRI contrast agents and their corresponding metal complexes which can be ionic or nonionic, physiologically tolerable and exhibit a low toxicity. A still further object of this invention is to provide metal chelating agents and their corresponding metal complexes in which the pharmacokinetics, physiological behavior, and biodistribution of these chelating agents and their corresponding metal complexes can be altered. Another object of this invention is to provide a method of synthesizing the chelating agents and their corresponding metal complexes. Moreover, another object of this invention is to provide chemically stable, physiologically tolerable chelating agents which can form complexes with metal ions, and in particular paramagnetic metal ions, and be used in vivo for MRI and other types of diagnostic imaging.